In medical practice vaginal infections are a common health hazard, since up to 95% of the patients go to the doctor due to vaginal flow. In primary health services, these infections affecting teenagers are found to be among the three topmost reasons for the visit, their incidence being much higher among the sexually active, although it has also been found among the girls who are not.
Normal vaginal secretions are inodorous, clear, viscous, with a Ph below 4.5, contain no necrophilia and do not flow during an examination with a speculum.
Among the factors favorable to vaginal infections we have poor genital-anal hygiene, a new sex partner or several of them, bathing in pools or tubs, pregnancy, diabetes, parasitic infections, urinary or fecal incontinence, stress, congenital malformation, frequent use of antibiotics, hormones, contraceptive preparations to be used orally or topically and vaginal, immune system deficiency, tight clothes, nylon underwear, using non-hygienic vaginal elements used for the application of products and so forth.
The most frequent vaginal infections are shown in the table below.
Clinical FrameworkEtiological AgentScarce whitish flow, pH < 4.5Candida albicansVulva itch and/orTrichomonas vaginallisirritation, erythema,profuse yellow flow, pH > 5Vulva itch, malodorousGadnerella vaginalliswhite-grayish flow, pH > 4.5(Haemophilus vaginallis)A smell of aminesAnaerobes(peptostreptococcusbacteria, porphyromons)after the addition ofpotassium hydroxideMobiluncus spp10%* presence of guide cellsMycoplasma hominis(Amsel's Criteria)Abnormal flow, post-coitalChlamidia trachomatisbleeding
Vaginal infection or vaginal flow syndrome is an infectious process characterized by one or more of the following symptoms: flow, vulva itch, burning, irritation, dysuria, dyspareunia and vaginal malodor; a microorganism is often to be found during vaginal infection, which originates mixed vaginal infections.
Vulvovaginitis, vulvitis and vaginitis are terms usually related to a swelling of the vagina or vulva, frequently caused by fungi, bacteria and parasites. By vulvovaginitis we understand the anomalous and irritating flow of secretion, whether malodorous or not, which produces local discomfort (itching or burning sensation) and which can be accompanied by dysuria and/or dyspareunia. Vulvovaginitis is the most frequent gynecological problem leading to a first visit to the doctor. 90% of females showing symptoms suffer from a bacteria sort of infection (mostly Gardnerellas), candidiasis or Trichomonas. The remaining 10% show a different set of symptoms: ETS, vaginal atrophy, allergies and chemically induced irritation. Candidiasic vulvovaginitis (VVC) is the most common cause of vaginitis in Europe. About 85-90% of the cases are due to Candida Albicans. The initial treatment makes use of topical agents.
Initial treatment make use of topical agents such as creams, vaginal tablets, and ovules for periods from 7 to 10 days, with the ovules and creams a recovery rate of no more than 75% percent is achieved. Due to the high level of discomfort for the patient, presence of adverse reactions or drug interactions, and the length of the treatment, other options for the treatment of vaginal infections have been sought, such as the use of systemic treatments and even the shortening of the period of the treatment itself. Some treatments may include the use of clotrimazole, miconazole, fenticonazole and nistatine. In the case of severe infections, recurrent ones or intolerance to vaginal application, the use of 400 mg a day of ketoconazole for 5 days or 200 mg of itraconazolere for 3 days or 400 mg 400 mg one day or 150 mg of fluconazole for one day is recommended. Drugs 49(6) 984-1006, 1995.
In the case of highly severe or chronic infections (4 or more episodes a year) an oral treatment is used and, to avoid a recurrence, 100 mg of ketoconazole a day is used during 6 months, a vaginal ovule of cotrimazol a month in the pre-menstrual stage during 6 months, or 200 mg of Itraconazole taken orally for 3 days during 6 cycles. Boletín 15 de Nov. 2002 Farmacoepidemiología
Bacteria induced vaginitis represents an alteration of the vaginal flora characterized by a decrease in the concentration of hydrogen peroxide produced by the lactobacilli and an increase in the prevalence of Garnerella vaginalis, and negative gram anaerobes which bring about the onset of malodorous flow without showing any signs of vulvo vaginal swelling. In bacteria induced vaginitis most of the lactobacilli disappear, vaginal pH increases and a pathogenic proliferation of other anaerobes bacteria is found. There are four bacteria associated to bacteria induced vaginitis: Gardenerella vaginalis, a facultative, fermentative anaerobes present in 40% of the average female, and the most commonly associated to this pathological condition (95%); Mobiluncus, Mycoplasma hominis as examples of negative gram anaerobes, and Peptostreptococcus . By oral via the preferred treatment is metronidazole: 50 mg taken orally, every 12 hours for 7 days. As alternative paths 2 g of metronidazole in an only dose or 300 mg of Clindamycin taken orally twice a day for a week are used.
Vulvovaginitis due to Trichomona is a process caused by mobile protozoa, flagellate and anaerobic called Trichomonas vaginalis and is acquired due to sexual intercourse. It is one of the main causes of vaginal infections. Fifty per cent of the patients (both male and female) are non symptomatic at the moment of the diagnoses. A third of them will develop the symptoms in the following 6 months if not treated. The most recommended pattern for the treatment is to take 2 grams of metronidazole in an only dose, whether male or female. By means of this therapeutic regime, and if also the sexual partner is involved, up to 85% of efficacy can be reached.
Taking into account that in the same woman several clinical variations may coexist and that the presence of a particular form of etiological agent cannot be fully determined by a gynecologic exam, the treatment should be approached as syndromes; concentrating on the most common infections associated to the vaginal flow syndrome: trichomoniasis, candidiasis and bacterial vaginosis as in those cases the infection is mixed.
The following table shows a resume of the most commonly prescribed treatments:
TABLE 1CandidiasisTrichomoniasisIsoconazole, 1%, vaginalMetronidazole, 250 mg, orally,cream, 7 to 14 days.3 × day, 7 daysMiconazole, cream or ovules, 7 daysMetronidazole, 2.0 g, orally,one doseTioconazole 6.5%, topical, one doseTinidazole, 2.0 g oral, one doseTerconazole, cream at 0.8%, 7 daysSecnidazole 2.0 g, oral, one doseFluconazole 150 g oral, one dayMiconazole + Tinidazoleassociated, vaginal cream, 7 daysItraconazole 400 mg-1 dayor 200 mg, 3 daysKetoconazole 200 mg, 2tablets, oral, 5 daysGardnerellaNeisseria/ClamydiaMetronidazole, 500 mg.Ceftriaxone 250 mg, IM one doseoral, twice a day, 7 daysTinidazole 2.0 g, oral, one doseAzithromycin 1.0 oral, one doseClindamycin 30 mg oral,Doxocilin 100 mg oral, 2 a day,2 a day, 7 days7 daysClindamycin 2% vaginal creamOfloxacin 300 mg oral 2 a day,3 to 7 days7 daysEritromicin stearate 500 mg oral4 times a day, 7 days
In the state of the art there are several published works where reducing the length of the treatment is being sought.
The U.S. Pat. Nos. 6,416,779, 5,120,735, 6,706,270 , 6,440,949 and 5,840,744 show different treatments, methods and compositions for intravaginal or transvaginal delivery, doses of a pharmaceutical agent to the vagina, nevertheless, it is important to be considered that the vaginal application may not be well accepted by the patient.
It is renown that the active agents with pharmaceutical qualities that have been developed or approved for their usage in the treatment of vaginal infections, include fungicides. It has been difficult to achieve an optimum effective potential in these compounds. They have been found, when used as gels, foams, creams, ovules and tablets, to decompose almost immediately after being inserted in the vaginal cavity, presenting minimum bioadherence to the walls of the vagina. It is believed that this happens due to their miscibility with water and/or the loss of their physical stability at 37° C. (body temperature). Becoming clear then that they exhibit limited effectiveness.
In U.S. Pat. No. 5,536,743, teaches a compound containing buffered metronidazol. However, this compound only treats bacterian vaginosis, for metronidazole is only effective against bacteria, not against fungus.
In U.S. patent applications no. 20030017207 and 20030064103, a compound containing an azole antifungal agent and a buffered active compound are described, as well as a pharmaceutically acceptable vehicle. The maintenance of the pH of the compounds of this invention is described as of vital importance herein, which should be kept preferably between approximately 2.5 and 5.5.
The buffering system is selected from the group that consists in gluconodeltalactone, acetic acid, fumaric acid, lactic acid, citric acid, propionic acid, malic acid, succinic acid, gluconic acid, ascorbic acid and tartaric acid. The azole active antifungal ingredient is selected from the group consisting in miconazole nitrate, terconazole, butaconazole, itraconazole, voriconazole, ketoconazole, econazole, tioconazole, fluconazole, posconazole, ravuconazole, clotrimazole and similar. The compound also contains a pharmaceutically acceptable vehicle as well as other components such as water, antioxidants, quelant agents, preservatives, oils, waxes, surfactants, emulsifiers, viscosity agents, solvents, mixing agents, solubilizers, bio-adhesives, muco-adhesives and similar agents.
In both documents, the amounts of said components to be used in the compound are clearly described, depending on the nature and consistency of the compound, which can be creams, ointments, ovules, gelified capsules, anhydride polymeric ovules of intravaginal application.
Hence, from the description of the abovementioned documents, it is drawn that the doses of the anti-fungic agent in the treatment of vaginal infections depends on the active ingredient used and its power. In these same documents, a therapeutically effective amount has been defined, given by the dosage found as preferable.
Another problem detected from the analysis of the state of the art, is the need to decrease the term of the treatment and find a form of application less uncomfortable and more effective for the population, in this sense, an attempt to solve this situation is found in the patent application MX No. 02/07641, codependent application to the present one, a fluconazole-and tinidazole pharmaceutical combination is described, its main feature being that the doses used are 150 mg fluconazole and 29 tinidazole for the treatment of infectious diseases in the female reproductive system.
Another case is the patent MX 188,752, wherein a therapeutic method for the treatment of vaginal infections is described and which includes using a combination of itraconazole-secnidazole. The treatment described in this patent is quite lengthy and demands taking 12 doses during the treatment for 3 days, which makes the fulfillment of the treatment by the patient questionable. Recovery is estimated at 77.77%.
Notwithstanding, and following the same research path, in the current investigation, it was amazingly found that the association of fluconazole and tinidazole in lower doses to those known, and administered in only one day of treatment in one or two events, for oral application, was discovered to improve in all aspects over the known treatments for mixed infections in the human reproductive system a feature that represents an edge over other lengthier treatments as it ensures that the patient will follow the treatment much more closely.
Contrary to expectations, diminishing significantly the dose did not affect the effectiveness of the fluconazole-tinidazole association, which held, therefore abating the secondary effects of these substances while keeping their effectiveness.
Another advantage the treatment has is that it is very useful for the medical personnel and communities that, due to various factors, can only access to a clinical diagnostic.
The composition is also effective in the prevention of such infections and provides a safe, effective, economical and provide effective relief from mixed infections in the human reproductive apparatus.
The compound is also effective in preventing such infections and provides a safe, efficient, economical relief of mixed infections in the human reproductive apparatus.
A further advantage is the higher possibility of therapeutic success, allowing for a quick lessening of the symptoms, with a good level of tolerance and acceptance from the part of the patient.